Innate immune receptors and autophagy: implications for autoimmune kidney injury

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http://www.kidney-international.org & 2010 International Society of Nephrology

Innate immune receptors and autophagy: implications for autoimmune kidney injury Hans-Joachim Anders1 and Detlef O. Schlondorff2 1

Department of Nephrology, University of Munich, Munich, Germany and 2Department of Medicine, Mount Sinai Medical Center, New York, New York, USA

Inflammation is the immune system’s response to infectious or noninfectious sources of danger. Danger recognition is facilitated by various innate immune receptor families including the Toll-like receptors (TLRs), which detect danger signals in extracellular and intracellular compartments. It is an evolving concept that renal damage triggers intrarenal inflammation by immune recognition of molecules that are being released by dying cells. Such danger-associated molecules act as immunostimulatory agonists to TLRs and other innate immune receptors and induce cytokine and chemokine secretion, leukocyte recruitment, and tissue remodeling. As a new entry to this concept, autophagy allows stressed cells to reduce intracellular microorganisms, protein aggregates, and cellular organelles by moving and subsequently digesting them in autophagolysosomes. Within the autophagolysosome, endogenous molecules and dangerassociated molecules may be presented to TLRs or loaded onto the major histocompatibility complex and presented as autoantigens. Here we discuss the current evidence for the danger signaling concept in autoimmune kidney injury and propose that autophagy-related processing of self-proteins provides a source of immunostimulatory molecules and autoantigens. A better understanding of danger signaling should enable us to unravel yet unknown triggers for renal immunopathology and progressive kidney disease. Kidney International (2010) 78, 29–37; doi:10.1038/ki.2010.111; published online 28 April 2010 KEYWORDS: autoimmunity; autophagy; danger signaling; glomerulonephritis; molecular mimicry; Toll-like receptor

Correspondence: Detlef O. Schlondorff, Department of Medicine, Mount Sinai Medical Center, Box 1243, One Gustave Levy Place, New York, New York 10029, USA. E-mail: [email protected] Received 3 February 2010; revised 5 March 2010; accepted 23 March 2010; published online 28 April 2010 Kidney International (2010) 78, 29–37

The integrity and survival of multicellular organisms depends on the initiation of an immediate host defense against infectious agents.1 Immediate pathogen recognition is guaranteed by innate pathogen recognition receptors, which can either activate complement-mediated killing or the activation of parenchymal and immune cells to produce cytokines and other mediators of inflammation designed to contain the infection (Table 1). Although most receptors are surprisingly specific for chemically defined pathogen-associated molecular patterns (PAMPs), the sum of the different receptor classes covers the entire spectrum of pathogens. Recently, it has been shown that endogenous molecules that are generated during tissue injury and labeled as dangerassociated molecular pattern (DAMP) molecules, can also activate pattern recognition receptors similarly to PAMPs, thereby offering a novel understanding of sterile types of inflammation (Table 2).2 DAMPs can originate from intracellular sources or can be generated from extracellular matrix degradation. As such DAMPs would normally not be available for presentation to immune sensors (Figure 1). However, DAMPs can be generated and released during cell stress, apoptosis, or necrosis due to traumatic, ischemic, toxic, or inflammatory tissue injuries. It is likely that DAMPs function as danger signals and that DAMP-mediated immune activation developed during evolution to aid danger control and tissue repair. If such a process escapes the normal control and/or suppression of an adaptive immune response to endogenous molecules, the recognition of PAMP and DAMP by receptors of the innate immune system could contribute to an autoimmune response. In this review we provide a conceptual outline by discussing examples from the field of autoimmune kidney disease: first, we introduce the concept that DAMP release from dying or generation by stressed cells can induce renal inflammation inside the kidney. Second, we discuss the possibility, that during an initial renal cell immune injury against foreign antigens, endogenous neoantigens may be generated. This can result in a process of antigen spreading, eventually provoking an autoimmune response contributing to the progression of renal disease by humoral and cellular immune mechanisms. Third, we discuss the concept of molecular mimicry of endogenous nucleic acids with viral nucleic acids with the potential of promoting lupus nephritis 29

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H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

Table 1 | Classes of innate and adaptive pattern recognition molecules Innate recognition molecules

Adaptive recognition molecules

Secreted to extracellular fluids

Pentraxins (CRP, SAP, pentraxin-3) Complement factors Mannose-binding lectin

IgA, IgM, IgG, IgE

Cell surface

Mannose receptor Scavenger receptors Complement receptors

T-cell receptors B-cell receptors (Ig) Antigen-presenting molecules

Compartment

Fc receptors Toll-like receptors Dectins Intracellular endosomes

Toll-like receptors

Intracellular cytosol

RIG-like helicases NOD-like receptors Inflammasome-activating molecules

MHC I, MHC II

Abbreviations: CRP, C-reactive protein; Ig, immunoglobulin; MHC, major histocompatibility complex; NOD, nucleotide-binding oligomerization domain; RIG, retinoic-acid-inducible protein; SAP, serum amyloid P.

through Toll-like receptors (TLRs) at the systemic level. Forth, we summarize data on the role of TLRs in mediating infection-associated flares of immune complex glomerulonephritis both at the systemic and the tissue levels. Finally, we discuss the potential role of autophagy in many of the above processes and in the eventual development of autoimmunity. DANGER-ASSOCIATED MOLECULAR PATTERNS CAN DRIVE RENAL AUTOIMMUNE TISSUE INJURY

The triggering events for the loss of tolerance, for example, against glomerular basement membrane (GBM) collagen components in anti-GBM disease, neutrophil or lysosomal lysosome-associated membrane protein 2 (LAMP2) antigens in antineutrophil cytoplasmic antibody–associated vasculitis, or chromatin in systemic lupus erythematosus (SLE), remain complex and difficult to sort out in individual patients. However, it is clear, that genetic and environmental factors need to overcome several check points before autoreactive lymphocyte clones are allowed to expand, so that rising serum concentrations of the respective autoantibodies become detectable by enzyme-linked immunosorbent assay.3 Although suspected for a long time, only recently has evidence been provided for molecular mimicry between infectious and endogenous antigens such as LAMP2 as a trigger for pathogenic antibodies in causing pauci immune glomerulonephritis.4 In addition, there is little doubt that autoantibodies against the a3NC1 domain of collagen IV are pathogenic in anti-GBM disease, because they bind to the intrarenal autoantigen and cause in situ immune complex formation, which activate FcgR and complement factors.5 This process usually leads to focal necrosis of the glomerular 30

Table 2 | Endogenous molecules proposed to function as DAMPs by activating TLRs or other receptors DAMP

Receptor

HMGB1 Heat shock proteins Hyaluronates, biglycan Heparan sulfate Fibrinogen Defensins U1snRNP-IgG DNA-nucleosomes-IgG Adenosine ATP S100 proteins dsDNA Cathepsin-B Uric acid crystals

TLR2, TLR4, RAGE, RIG TLR2, TLR4 TLR2, TLR4 TLR4 TLR4 TLR4 TLR7 (FcR/BCR) TLR9 (FcR/BCR) A1/A2A/A2B/A3 P1/P2X/P2Y RAGE AIM2 – IL-1R NALP3 – IL-1R NALP3 – IL-1R

Abbreviations: AIM, absent in melanoma; BCR, B-cell receptor; DAMP, damageassociated molecular pattern; HMGB, high-mobility group B; Ig, immunoglobulin; IL, interleukin; NALP, Nacht domain-leucine-rich repeat- and PYD-containing protein; RAGE, receptor for advanced glycation end products; TLR, Toll-like receptor.

tuft, histopathologically referred to as necrotizing glomerulonephritis.6 Podocytes and parietal epithelia are activated to proliferate leading to crescentic glomerulonephritis.7 Both types of lesions involve the local production of chemokines, which enhance the influx of antigen-specific T cells and macrophages into the glomerular compartment or the periglomerular space. Resident cells, as well as infiltrating cells, also produce proinflammatory cytokines such as IL-12, TNF-a, and interferon-g (IFN-g). These cytokines will drive T-cell responses toward the Th1 phenotype and the resulting cellular immune response. Such T-cell responses are usually counterbalanced by regulatory T cells in secondary lymphoid organs as well as at the tissue level. However, in experimental anti-GBM disease CD4 þ CD25 þ Foxp3 þ CD69-CD45RBlow regulatory T cells were less potent in suppressing nephritis as compared with regulatory T cells from nonnephritic mice.8 Crescentic glomerulonephritis has therefore been classified as the renal manifestation of a Th1-like delayed type of hypersensitivity reaction.9 Antineutrophil cytoplasmic antibody–associated vasculitis is associated with comparable glomerular pathology, even though termed pauci-immune, that is, few, if any, glomerular immune complex deposits can be seen.6 In antineutrophil cytoplasmic antibody–associated vasculitis neutrophils disrupt the endothelium in the microvasculature, causing focal glomerular necrosis by a combination of the release of toxic granule contents, ischemia, and complement activation.6 The novel danger signaling adds to these mechanisms and highlights the proinflammatory role of dying cells.10 Although early phases of apoptotic cell death with the rapid removal of apoptotic bodies may avoid the release of intracellular DAMPs and a subsequent inflammatory response, late apoptotic or necrotic cells release the content into the extracellular space.2 Here they can bind to pattern recognition receptors either directly on the cell surface or, after endocytosis, in the endosomal compartment of immune and nonimmune cells (Figure 1). Furthermore, the local activation of matrix-degrading Kidney International (2010) 78, 29–37

H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

Stranger model

Danger signal

Pathogen Necrotic cell PAMPs

DAMPs

APC

Avoiding immune activation Impaired clearance Apoptotic cell

Matrix degradation

Hidden DAMPs

Phagocytosis

APC activation – Il-10 –TGF-β

Lymphocyte

+Costimuli T cell Activated APC

Clonal proliferation

Phagocyte Anergy Apoptosis Ignorance

Figure 1 | Immune recognition of extrinsic and intrinsic dangers. Pathogens release pathogen-associated molecular patterns (PAMPs) that activate antigen-presenting cells (APCs) and nonimmune cells through pattern recognition receptors. The maturation of, e.g., APC-like dendritic cells leads to antigen presentation in the presence of costimulatory molecules that set off adaptive immune responses involving clonal expansion of antigen-specific T and B cells. Necrotic cells release intracellular molecules that can activate the same classes of immune receptors and thereby act as danger-associated molecular patterns (DAMPs). This mechanism can explain sterile types of inflammation that present clinically like infectious diseases such as a gout attack (DAMP ¼ uric acid crystal) or postischemic tissue inflammation. In SLE nuclear particles containing immunostimulatory nucleic acids function as adjuvant-like DAMPs in addition to their role as autoantigens. Apoptotic cell death avoids DAMP release and inappropriate immune activation. Vice versa, genetic defects in apoptosis or the rapid clearance of apoptotic cells by phagocytes predispose to chronic inflammatory autoimmune diseases such as SLE because secondary necrosis of apoptotic cells causes DAMP release.

enzymes around apoptotic and necrotic cells can generate fragments of extracellular matrix, such as hyaluronates and biglycans, which can serve as DAMPs.2 Many studies of the heterologous model of nephrotoxic serum nephritis in mice lacking TLR2 or TLR4support the role of DAMPs in glomerular disease. In these knockout mice full-blown crescentic glomerulonephritis is prevented by reduced activation of proinflammatory mediators in the glomerular compartment.11,12 Some studies have reported similar results by using the autologous serum nephritis in TLR-deficient mice or by co-injecting TLR agonists during the immunization phase.13,14 Furthermore, there is evidence from chimeric mice that TLR2 on both intrinsic glomerular cells and on leukocytes is involved in this process.12 The interpretation of these studies must take into account that Kidney International (2010) 78, 29–37

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TLR activation modulates the immunization phase and the adaptive immune response, which affects kidney disease by additional extrarenal mechanisms. Although the role of TLR2 and TLR4 in crescentic glomerulonephritis is consistent with their role for sterile inflammation in postischemic acute renal failure,15–17 a potential role of endogenous RNA in activating TLR3 during crescentic glomerulonephritis is less likely, as serum nephritis could be induced in mice deficient in TRIF, the adapter protein required for TLR3 signaling.18 Necrotic cells activate primary mouse mesangial cells preferentially through TLR2/MyD88 rather than TLR3/TRIF, making endogenous dsRNA as a relevant DAMP for TLR3 ligation less likely.18 One may speculate that HMGB1, hyaluronic acid, biglycan fragments, or fibrinogen function as endogenous TLR2 and TLR4 agonists in glomerular cells, as shown for fibrinogen activating TLR4 in podocytes.19 Although selfRNA does not seem to trigger TLR3/TRIF signaling in antiGBM nephritis, nuclear HMGB proteins can exert their effect as cofactors for RNA and DNA recognition through TLR7 and TLR9 as well as TLR-independent nucleic acid recognition pathways.20 Whether such a potential process contributes to anti-GBM nephritis has not yet been formally examined. However, this mechanism could serve as an explanation for the intraglomerular induction of type I IFNs, which promote glomerular inflammation in autologous nephrotoxic serum nephritis.21 Thus, glomerular cell injury and extracellular matrix modification have the potential to activate innate immune responses through the release of intracellular DAMPs, which can activate pattern recognition receptors such as TLR2 and TLR4 on adjacent glomerular immune and nonimmune cells. The nature of these glomerular DAMPs remains to be defined in detail, but data from other areas provide sufficient evidence for the dangersignaling hypothesis as a whole.2,10 EPITOPE SPREADING AS A MECHANISM FOR AN IMMUNE RESPONSE IN RENAL DISEASE

The role of T cells and specifically CD8 þ T cells in autoimmune-mediated glomerular and tubulointerstitial disease has been discussed for decades.22 Lately, clear experimental evidence for the significance and mechanisms of T-cell involvement in glomerular and tubulointerstitial disease has been forthcoming, as recently reviewed by Sung and Bolton.22 This process may also link glomerular pathology and proteinuria to progressive interstitial disease. Subsequent to injury in the glomerulus or in the tubulointerstitium neoantigens can be generated leading to epitope spreading with generation of neoantigens, which are then presented by dendritic cells to T cells either within the kidney or in draining lymph nodes.23–26 Potentially, such neoantigens could at the same time exert their effect as DAMPs, and activate the innate immune response through TLRs on mesangial, epithelial, interstitial, and endothelial cells as well as on macrophages and dendritic cells. The combined activation of an innate and adaptive immune response would lead to a propagation and spreading of the disease from the 31

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glomerulus to the tubular and interstitial compartment. Recently, Macconi et al.27 showed, in a model of proteinuria secondary to reduction in kidney mass, that filtered albumin was partially processed by tubular epithelial cells and subsequently by dendritic cells, resulting in major histocompatibility complex (MHC) I-mediated antigen presentation to CD8 þ T cells in the regional lymph nodes. Cytotoxic CD8 þ T cells specific for renal antigens then propagated renal damage. This mechanism provides a novel explanation for the progression of renal diseases by autoimmune renal injury. This concept is further supported by a study using a transgenic mouse model with podocyte-specific expression of a neoantigen.28 Thus, intrarenal epitope spreading involving intrinsic renal cells, dendritic cells, and T cells could contribute to an autoimmune type of kidney injury. The potential roles of the innate immune system and TLRs in this process, as well as the contribution of autolysosomal processing of neoantigens, have not been examined as yet. ENDOGENOUS NUCLEIC ACIDS DRIVE LUPUS NEPHRITIS BY TRIGGERING ANTIVIRAL IMMUNITY

Lupus nephritis is characterized by a loss of tolerance and a polyclonal autoimmune response against multiple nuclear and chromatin-related autoantigens, which are ubiquitous, albeit hidden inside cells. Hence, nuclear autoantigens reach the extracellular space only when apoptotic cells are not properly removed and undergo secondary necrosis. This process will foster the formation of immune complexes containing autoantibodies and nuclear autoantigens that contain immunostimulatory nucleic acids.29 Circulating immune complexes tend to deposit in glomeruli and activate FcgR and complement, either along the inside or the outside the filtration barrier as well as in the mesangium, causing a spectrum of different histopathological manifestations.29 Especially, diffuse proliferative lupus nephritis is associated with mixed macrophage, T-cell, and B-cell infiltrates due to local expression of proinflammatory cytokines and chemokines. A new entry into the pathogenesis of lupus nephritis is the concept that the immune dysregulation in SLE is largely homologous to antiviral immunity. For example, transcriptome profiles of peripheral blood monocytes from lupus patients show a profound induction of type I IFN and IFNrelated genes, recalling a classical antiviral response pattern.30 Immune complexes containing nuclear lupus autoantigens have the potential to activate TLR7 and TLR9 on plasmacytoid dendritic cells and B cells initiating a response program comparable to that during viral infection.30,31 This was shown for immune complexes containing chromatin or hypomethylated CpG-DNA that activate TLR932 as well as for immune complexes containing U1snRNP that activate TLR7.33,34 In addition, nuclear HMGB proteins can function as cofactors for RNA and DNA recognition through TLRdependent as well as -independent nucleic acid recognition pathways.20 The same IFN signature was found by transcriptome profiling of glomerular isolates of human renal 32

H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

biopsies, which may originate from either glomerular leukocytes or intrinsic renal cells.35 In fact, complexed RNA or dsDNA can trigger the production of large amounts of IFN-a and IFN-b as well as multiple IFN-dependent genes in glomerular endothelial cells and mesangial cells.36–38 As endothelial cells and mesangial cells lack TLR7 and TLR9, these responses rather involve TLR-independent nucleic acid recognition pathways.36,38 Nevertheless, self-RNA recognition by TLR7 has a dominant role in mediating SLE disease activity.31,39 TLR7 deficiency40,41 or TLR7 blockade42 prevents proliferative lupus nephritis in mice by specifically impairing the production of RNA autoantibodies. Furthermore, lupus nephritis becomes more severe when TLR7 signaling is enhanced, for example, by TLR7 gene duplication43 or by genetic elimination of TLR7 inhibitors such as SIGIRR44 or TLR9.45 Hence, self-nucleic acid-induced ‘pseudoantiviral’ immunity translates into autoimmune tissue damage. The functional importance of type I IFN was, also shown by studies, that observed almost complete suppression of lupus nephritis in mice deficient in the type I IFN receptor.46–49 Can this concept be translated to human lupus? Type I IFN expression levels are elevated in SLE patients with active disease and dropped on immunosuppressive therapy.50,51 Furthermore, type I IFN cause ultrastructural changes in lymphocytes and endothelial cells, that is, the tubuloreticular structures.52 These have only been observed in three cohorts of patients: (1) patients with viral hepatitis treated with IFN-a;53 (2) in renal biopsies of patients with HIVAN;54 (3) and in blood lymphocytes of SLE patients.55 In lupus nephritis biopsies these structures are also commonly noted in glomerular endothelial cells and are referred to as ‘lupus inclusions’.56 Lupus inclusions seem to represent a specific type of IFN-a-induced protein assembly in the cytosol of cells. As such they do not only serve as a diagnostic tool57 but also as a hint for the pathogenic role of IFN induction in lupus immunopathology. RNA and DNA lupus autoantigens have additional, adjuvant-like, immunostimulatory properties by binding to viral nucleic acid recognition receptors comparable to viral particles. This may explain the overlapping clinical presentations of viral infection and SLE, and suggest a new pathogenic concept of lupus nephritis.58 HOW INFECTIONS CAN TRIGGER FLARES OF AUTOIMMUNE KIDNEY DISEASE

It is a common clinical observation that various infections induce flares of lupus nephritis, of renal vasculitis, of IgA nephritis, or of other forms of immune complex glomerulonephritis. Recently, a direct molecular mimicry between a pathogen-derived protein and a lysosome chaperone LAMP2 protein in endothelial cells was identified, and showed to function as an autoantigen, thereby triggering a pauci immune focal necrotizing glomerulonephritis.4 Molecular mimicry had been discussed as a mechanism for vasculitis for many years, but had never been clearly shown. Besides such direct and specific activation of the immune system by Kidney International (2010) 78, 29–37

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H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

Table 3 | Effects of transiently exposing MRL(Fas)lpr mice with lupus-like immune complex glomerulonephiritis to various TLR agonists PRR Ligand Mesangiolysis Proteinuria Macrophages Inflammation Anti-dsDNA Glom. C3 Lymphoprol.

TLR2 lipoprotein

TLR3 dsRNA

TLR4 LPS

TLR7 ssRNA

TLR9 CpG-DNA

?, DAI dsDNA

RIG-I 3P-RNA

 +++ + ++ + + +

+ + + ++   

 + ++ ++ + + +

 + + ++ + + +

 + ++ +++ +++ ++ +++

 + + ++ + + +++

 + + ++ + + 

Abbreviations: C3, complement factor 3; ds, double stranded; glom., glomerular; lymphoprol., lymphoproliferation; 3P-RNA, 50 -triphosphate RNA; PRR, pattern recognition receptor; ss, single stranded.

molecular mimicry, other potential mechanisms for infection-associated activation of the immune response and resultant renal immunopathology exist. For example, phagocytosis of infected apoptotic cells by dendritic cells triggers the expansion of autoimmunity-related Th17 T cells, whereas phagocytosis of noninfected apoptotic cells favors the expansion of immunosuppressive regulatory T cells.59 During systemic infection circulating PAMPs activate immune cells and nonimmune cells throughout the body, which affects immune responses at the systemic as well as at the local level. For example, vascular leakage is a hallmark of sepsis or noninfectious tissue injury, because PAMPs increase vascular permeability by activating TLRs on vascular endothelial cells.60,61 The same mechanism enhances proteinuria during immune complex glomerulonephritis as shown for systemic LPS exposure from Gram-negative bacteria11,62,63 or lipoprotein from Gram-positive bacteria.63 These bacterial cell wall components enhance the permeability of glomerular endothelial cell and podocyte monolayers by activating surface TLR2 and TLR4.63,64 Viral nucleic acid complexes have a similar effect when they reach the intracellular cytosol and activate cytosolic viral nucleic acid sensors.36 These experimental findings may explain why endotoxinemia or sepsis produces a mild and short-lasting proteinuria in humans.65 Such PAMPs may produce stronger and longerlasting renal dysfunction in patients with preexisting glomerular diseases and a preactivated and thereby hyperresponsive glomerular endothelium. In addition, other PAMPs can activate TLRs and other receptors of the innate immune system on glomerular cells to secrete proinflammatory cytokines such as IL-6 and TNF-a, thereby enhancing glomerular inflammation.66–69 As mentioned earlier, viral nucleic acids may also trigger glomerular expression of type I IFN, which adds to the proinflammatory microenvironment.37,38 The PAMPs as well as the secreted mediators also activate resident dendritic cells as well as the leukocytic cell infiltrate, which is usually present in chronic nephropathies.70 These activated intrinsic renal parenchymal cells and intrarenal immune cells also produce proinflammatory chemokines such as MCP-1/CCL2, CCL5/RANTES, and CXCL10/IP-10, which will foster additional leukocyte recruitment and renal damage. The potential of TLR agonists to trigger disease activity of murine lupus-like immune complex glomerulonephritis was assessed in MRL(Fas)lpr Kidney International (2010) 78, 29–37

mice. Agonists for TLR2, TLR3, TLR4, TLR7, RIG-I, and cytosolic DNA sensors had a similar potential to aggravate glomerular inflammation (Table 3).63,71–74 The TLR9 agonist, unmethylated CpG-DNA, which may derive from viruses or bacteria, was unique in inducing crescentic glomerulonephritis and renal vasculitis in nephritic MRL(Fas)lpr mice,74 and was the only TLR agonist that could trigger the onset of glomerulonephritis in young MRL(Fas)lpr mice that had not yet developed SLE-like autoimmunity.75 The latter is remarkable because most reports are consistent in that TLR9 expression is restricted to extrarenal plasmacytoid dendritic cells, macrophages, and B cells in healthy mice.76 Obviously, the activation of immune cells outside the kidney contributes to the onset of renal disease. In fact, CpG-DNA and—to a lower extent most other PAMPs—enhanced immune complex disease by increasing serum cytokine levels, autoantibody levels, and glomerular immune complex deposits in MRL(Fas)lpr mice (Table 3). Only the TLR3 agonist dsRNA aggravated lupus nephritis by activating mesangial cells rather than by affecting immune complex disease.72 Thus circulating PAMPs will not only activate an antigen-specific adaptive immune response, but will at the same time serve as nonspecific adjuvants, thereby enhancing the response of preexisting B- and T-cell clones fueling the autoimmune diseases. In addition, circulating PAMPs can activate renal parenchymal cells and intrarenal immune cells to enhance renal inflammation. AUTOPHAGY, A POTENTIAL LINK TO AUTOIMMUNITY

Autophagy may be an as-yet-underappreciated link between the innate and adaptive immune responses and danger signaling. Autophagy was initially recognized as a pathway to salvage cellular proteins during stress, such as starvation, to guarantee cell survival.77,78 As such, autophagy represents an early step in the organism’s strategy to promote survival, that, if it fails, will result in apoptosis or even necrosis. During the previous years it has become ever more apparent that autophagy is also broadly associated with many steps of immune responses.79–81 Pathways of autophagy

All mammalian cells undergo constitutive autophagy to some extent, that is, they engulf and digest endogenous cytosolic proteins, membrane particles, or intracellular organelles.77 33

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H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

TLR

Autophagosome

PI3 Kinase Rapamycin

Microautophagy

Lysosome

Chaperonemediated autophagy

TOR Atg proteins LAMP-2A TLR Cytoplasm Parts of membranes intracellular organelles (e.g. mitochondria)

Macroautophagy

Chaperone Unfolded substrate protein Lysosomal hydrolase

Developing autophagosome

MHC II

Autolysosome

Figure 2 | Schematic illustration of macro-, micro-, and chaperone-mediated autophagy and the formation of autolysosomes. Under normal conditions and in the presence of growth factors, PI3 kinase will be active and stimulate TOR (target of rapamycin), which will inhibit ATGs and thereby autophagy. Decreased PI3 kinase activity would result in less TOR activity, less ATG inhibition, and enhanced autophagy. Rapamycin as an inhibitor of TOR would also activate ATGs and thereby autophagy.

During starvation macro-autophagy is initiated by diminished phosphatidylinositol-3 kinase (PI3K) activation due to loss of growth factors. PI3K normally activates the mammalian target of rapamycin. Decreased mammalian target of rapamycin activity secondary to diminished PI3K activity or inhibition of mammalian target of rapamycin by, for example, rapamycin will induce autophagy,77 which may account for beneficial or detrimental effects in the kidney. The formation of macro-autophagosomes proceeds by invagination of newly formed double membranes to form intracellular vesicles. This involves a number of autophagyrelated gene (Atg) products.77 During the formation of the autophagosome portions of the cytosol as well as entire organelles, such as intracellular membrane vesicles or mitochondria, can be engulfed. The autophagosome then fuses with lysosomes, forming the autolysosome (Figure 2). In chaperone-mediated autophagy specific cytosolic proteins are recognized by chaperone complexes, containing components of the heat shock cognate protein HSC70 and LAMPs, enabling docking to lysosomes and transfer of the captured proteins for lysosomal degradation (Figure 2). Within the lumen of the autolysosome, membrane structures and proteins are degraded by lysosomal proteases, which are activated by the acid pH generated by proton pump ATPases of autolysosomes.77 AUTOPHAGY AS PART OF THE IMMUNE RESPONSE

In dendritic cells macro-autophagy and chaperone-mediated autophagy can deliver both foreign and self-proteins to autolysosomes, where they are processed and may eventually come in contact with and bind to MHC class II in a specialized compartment.82 In support of this concept is the observation that more than 50% of autophagosomes merge and colocalize with the MHC II loading compartment.83 Initial evidence for macro-autophagy also contributing to 34

MHC class I cross-presentation has been provided for tumor antigens84,85 as well as for intracellular pathogens.86–90 Within the autolysosomes pathogens can interact with membranebound and cytosolic receptors of the innate immune system, which reside in endosomal compartments (such as TLR3, -4, -7, -9). Furthermore, cytosolic receptors such as retinoic acid-inducible gene I (RIG-I), such as helicase receptors, and other cytosolic receptors for RNA and DNA and NOD receptors can interact with components of autophagy.86,91–93 Potentially, autophagy pathways may also deliver DAMPs, generated by stressed or dying cells, to innate immune receptors, such as TLRs present in autolysosomes.20,94–96 However, activation of a number of these receptors can in turn enhance autophagy thereby further propagating the process.80,92,97 The activation of receptors of the innate immune system would then result in a proinflammatory response as described above. Thereby, autophagy will establish a connection between innate and adaptive immune responses by delivering either infectious agents or modified self-proteins and/or DNA or RNA to autolysosomes for processing as foreign or self-antigens. Autophagy also influences B- and T-cell homeostasis, including Th1/Th2 polarization, and tolerance.79,81,95,98,99 Under normal conditions autophagy is involved in the delivery to and presentation of self-antigens by MHC II, contributing to the induction and maintenance of CD4 þ T cell tolerance.79,83,90 Potentially, enhanced autophagy during cell stress together with a change in the cytokine milieu may lead to a weakening or breakdown of tolerance and thereby to the development of autoimmunity.81,95 In this context, the description by Kain et al.4 of LAMP2 as a novel autoantigen in pauci immune vasculitis is of interest. This ‘autoantigen’ is a major component of chaperone-mediated autophagy for the delivery of proteins to the autolysosome.77 Kain et al.4 showed that in pauci immune vasculitis LAMP2 becomes an autoantigen. The authors attribute this to molecular mimicry with a bacterial antigen. Alternatively, one might speculate that as both the bacterial antigen and Lamp2 will end up in the autolysosome during infection, the local control of tolerance might be overwhelmed in the autolysosome, resulting in processing not only of the bacterial antigen, but also of the LAMP2 self-antigen.4 This would then cause an adaptive immune response not only to the invading bacteria, but also to the autophagosomal LAMP2. Obviously this only represents a hypothesis at present. In B cells autophagy facilitates the interaction of the B-cell receptor with TLR9 in an autolysosome-like compartment.79,81,95,98,99 This results in enhanced production of antibodies to DNA antigens, especially in autoimmune diseases such as systemic lupus.100 The ligand for the TLR9 activation could consist of DNA complexed with HMGBs, both being released from dying cells.2 Potentially, such mechanisms could also contribute to an autoimmune response during progressive tissue damage. For example, protein and lipid overload of tubular epithelial cells during proteinuria or prolonged cell stress of epithelial and Kidney International (2010) 78, 29–37

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H-J Anders and D Schlondorff: Autophagy in renal autoimmunity

endothelial cells due to hypoxia/ischemia and endoplasmic reticulum stress could enhance the formation of autophagosomes and autolysosomes, and generation and release of DAMPs. In adjacent dendritic cells, autolysosomal proteolysis of DAMPs could potentially generate neoantigens binding to MHC class I or II molecules for surface presentation and subsequent T-cell activation.79 This may represent an intriguing possibility linking cellular protein overload, endoplasmic reticulum stress, hypoxia, and other mechanisms of local cell injury during kidney disease to autophagy and a resulting autoimmune response as part of progression of renal diseases. Recently, epitope spreading was identified as an important factor linking dendritic cell–T cell interaction during glomerular injury to the subsequent tubulointerstitial progression of disease.4,28 If, and how, autophagy may contribute to molecular mimicry of pauci-immune vasculitis, loss of tolerance, and to epitope spreading in progression of renal disease should be an area of future research.

autophagy. Perhaps we have already, but unknowingly, benefited from the modulation of autophagy by rapamycin therapy. Thus, research in autophagy and immune-mediated renal disease may already have started under a different label. DISCLOSURE

The authors declared no competing interests. ACKNOWLEDGMENTS

HJA was supported by grants from the Deutsche Forschungsgemeinschaft (AN372/9-12 and GRK 1202). DS was supported by a grant from the National Institutes of Health, USA (R01 DK 081420). We thank Christoph Ro¨mmler for his help with Figure 1. REFERENCES 1. 2. 3.

SUMMARY AND FUTURE DIRECTIONS

Autophagy is involved in many physiological processes, ranging from cell metabolism to immune function and eventually to protection from cell death. As such autophagy is also involved in the pathophysiology of many diseases. In the kidney autophagy has been shown to protect against acute tubular injury and lately to protect glomerular podocytes from the wear and tear associated with permselective ultrafiltration.101 As such, autophagy may also be important as a nonselective bulk protein degradation system, a function that may be especially pertinent for proteinuric renal disease. In this context autophagy may deliver filtered as well as locally generated DAMPs for autolysosomal processing by tubular epithelial cells, as well as by local dendritic cells and macrophages. Obviously, this process is similar to the processing of infectious agents and delivery of PAMPs to the autolysosomal compartment. During this process DAMPs and PAMPs interact with TLRs and other receptors of the innate immune system followed by immune activation, local inflammation, and acquired immunity. Furthermore, neoantigens, including autoantigens, are generated and presented to MHC II and I in autophagy-associated compartments, resulting in loss of tolerance and a full-blown autoimmune response. Support for these concepts is forthcoming from a number of experimental immunological studies. In the case of autoimmune kidney diseases, there exists only some early, and mostly indirect evidence, for these concepts, which have not yet been fully tested in kidney diseases. We anticipate that new studies will examine the role of autophagy not only in acute tubular and glomerular epithelial injury, but also in chronic proteinuric and immunological kidney injury. In this context it may be worthwhile recalling that rapamycin is not only an immunosuppressive drug, but also an autophagy enhancer. Potentially, many of the beneficial effects of rapamycin in experimental kidney disease, and even in patients treated with rapamycin, may be unrelated to the immune-suppressive effect of the drug, but may relate to rapamycin activation of Kidney International (2010) 78, 29–37

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